Synthesis of vitamin a



Patented Sept. 11, 1951 2,557,572

UNITED STATES PATENT OFFICE 2,567,572 SYNTHESIS OF VITAMIN A Nicholas A.Milas, Belmont, Mass} assignor to Research Corporation, New York, N. Y.,a corporation of New York No Drawing. Application November 28, 1947,Serial No. 788,683

6 Claims. (Cl. 260-617) 2 In my Patents Nos. 2,369,156, 2,369,160, and vcordance with the present invention the acetylene others of the series2,369,156-2,369,168 I have carbinol of compound XIII, i. e. the compoundshown the synthesis of the compound referred CH: to therein as compoundXIV and having the formum 5 11c=o- CH=Cl I:

CH: CH: H

CH: cm XII H which may be obtained as described in said pat- H H m entsis first rearranged by treating it in an aqueous solution of a mineralacid such as sulfuric z acid to form the enyne carbinol compound XEIaXIV as follows: by allowing the aldehyde compound 5% V cm x11 CH: 15Compound also. HCECC=CE-CH=O H H cn=c11-dn-cno The Grignard of compoundXIIa is then reacted H on, with the aldehyde compound IV (which may bemade by application of the Darzens synthesis to p-ionone) as follows:

I i p T OH! to react with the Grignard compound Compound W BrMgcEC OMgBrEH Grignard of Kim HaC=CH CECMgBr Hydmysiswim M831 NHiCl or tartaricacid x111 CH: CH:

e on, CH; Compound IHV was select1vely hydrogenated A to convert theacetylene bond thereof into an CH=CH HCH C=C =CH-CHOH olefin bond andthe resulting glycol compound H H2 -CH3 CH3 CH3 HH 'HHH B H: c=c-'c-oc=c-J:c=cm XIVa H B and the resulting compound XIVa is partially HCH: hydrogenated with Pd on CaCOa to convert the acetylene bond thereofinto an olefine bond and xv produce the following compound 0 on wasrearranged and dehydrated to the compound 40 Om CH 3 CH H2CH=CH-CHCH-CH=CH-C=CHCH1OH H H J) H H H e H H H C: =CC=C =C-CH:B1' H CHCompound XIVb is then treated with pyridine x hydrobromide in pyridineto form vitamin A by successive treatments with a phosphorus haldirectlyVitamin A is formed from compound ide in the presence of pyridine andwith potas- XIVb y following a y of the othe methods 01 sium hydroxidein alcohol. Compound X was dehydration described in the above-mentionedthen converted to vitamin A by any one of seve patents. eral proceduresdisclosed in said patents. The invention is illustrated by the followingThe present invention relates to a direct procspecific examples:

ess for the production of compound X. In ac- Rearrangement of compoundXII to compound XIIG.A mixture of 20 g. of compound X11 and 200 cc. ofsulfuric acid was shaken in nitrogen for 20 hours. At the end of thistime a bluish layer separated above the aqueous layer and had a distinctodor of a vinyl acetylene. The entire mixture was neutralized withsodium bicarbonate and extracted with ethyl ether, the extract driedwith anhydrous magnesium sulfate and filtered. After removal of theether the residual liquid was fractionated under a reduced pressure andthe fraction boiling at 65-66" mm.) collected and analyzed; 77.131.4782; d4 0.8577; calcd. MR, 28.97; found MR, 31.69, showing anexaltation of 2.72. This exaltation is due to the conjugation of theolefin with the acetylene bond. The unrearranged product had a normal Maof 28.79. The rearranged product has also a Zerewitinoif value of 1.97,as against the calculated value of 2.00.

Preparation of compound XIVa. from compounds IV and XIIa.-A Grignard wasprepared in the usual manner in about 150 cc. of anhydrous ethyl etherfrom 7.2 g. of ethyl bromide and 1.6 g. (10% excess) of magnesium. Themixture was cooled to 0 and to it was added in an atmosphere of nitrogen3.1 g. of the vinyl acetylene carbinol in an equal volume of anhydrousether. In order to effect the complete formation of the Grignard ofcompound XIIa, the mixture was allowed to stir in nitrogen overnight,then refluxed gently for two hours. It was then cooled to 0 and to itwas added 6 g. of the aldehyde 1V in an equal volume of anhydrous ether.The mixture was then allowed to stir overnight at room temperature, thenhydrolyzed with excess aqueous tartaric acid solution. The etherealsolution was separated, washed with water and dried over anhydrousmagnesium sulfate. When the mixture was filtered and the ether removedunder a reduced pressure, a yellowish highly viscous liquid (about 7 g.)remained. To remove volatile materials, this liquid was subjected to avacuum of 10 mm. at a temperature of 100 for one hour. It was thenanalyzed and found to have the expected hydrogenation and Zerewitinoffvalues for compound ma. Attempts to crysstallize it were not successful.

The successive hydrogenation and dehydration of compound XIVa, formed asdescribed above, to the production of compounds XIVb and vitamin A neednot be described in detail because methods for the carrying out of thesesteps on similar compounds are amply disclosed in said patents.

Iclaim:

1. Process which comprises reacting a compound of the formula wherein Xstands for halogen with a compound of the formula obtainable byapplication of the Darzens synthesis to 18ionone.

2. Process as defined in claim 1 in which the reaction product ishydrolyzed to the formation of the compound of the formula 6. As a newproduct the compound of the formula NICHOLAS A. MILAS.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,369,161 Milas Feb. 13, 19452,451,739 Isler Oct. 19, 1948 OTHER REFERENCES Cymerman et al.: Jour.Chem. Soc. (1945), pages -94.

Isler et al.: Helv. Chim. Acta, vol. 30, 1911-27 (1947).

Isler et al.: Barell Festschrift (1946), 33-44.

1. PROCESS WHICH COMPRISES REACTING A COMPOUND OF THE FORMULA
 5. AS ANEW PRODUCT THE COMPOUND OF THE FORMULA